Method of treating hypertension with morphanthridines

ABSTRACT

The inventive method comprises administering a safe and effective amount of a selected morphanthridine to a hypertensive animal to effect a lowering of blood pressure. Representative of the compounds that can be used in the method are 2-chloro-11-(3dimethylaminopropylidene)-morphanthridine, 11-(3dimethylaminopropyl)-morphanthridine and 11-(1-methyl-4piperidylene)-morphanthridine.

United States Patent Dage [451 Sept. 19, 1972 [54] METHOD OF TREATING[56] References Cited UNITED STATES PATENTS 3,591,691 7/1971Gansseretal. ..424/244 gg f Deer 3,530,219 9/1970 Walker ..424/244 4Prima Examiner-Sam Rosen 7 1 I Assign $232; We ompany New Attorney-T. F.Kryshak and M. L. Youngs AB [22] Filed: June 24, 1970 [57] STRACT Theinventive method comprises administering a safe [21] Appl 49,502 andeffective amount of a selected morphanthridine to I a hypertensiveanimal to effect a lowering of blood 52 US. Cl ..424/244 PressureRepresentative of the compounds that can 151 1111.01. ..A6lk 27/00 beused in the methd are [58] Field of Search ..26()/239 D; 424/244dimethylamimpmpyldene*mmphamhridim,

dimethylaminopropyl)-morphanthridine and 1 1-(1-methyl-4-piperidylene)-morphanthridine.

6 Claims, No Drawings METHOD OF TREATING HYPERTENSION WITH responding5,6-dihydromorphanthridines with active MORPHANTHRIDINES manganesedioxide.

DESCRIPTION OF THE INVENTION The described process may be illustrated asfollows:

The present invention relates to a method of treating 5 R I vhypertension in animals by administering to the animals =N\ amorphanthridine of the formula X y X Y 1|}, \z/ \N/ l0 7, V, X y The5,-dihydromorphanthridine starting materials may be prepared asdescribed in US. Pat. Nos.

\Z/ 3,267,094 and 3,153,652.

Representative of the compounds which may be emin which 2 is ployed inthe practice of the present invention are thefollowing: l l-(l-methyl-4-piperidylene )-morphanthridine,

H 2-chloro-l l-( l-methyl-4-piperidylene)- C H C y morphanthridine, N NH Z-trifluoromethyl-l l-( l-methyl-4-piperidylene)- 1i {imorphanthridine,

1 l-( l-ethyl-4-piperidylene )-morphanthridine, 2-chloro-l l-(1-ethyl-4-piperidylene X and Y are members of the group consisting of pnt fl r m hy -I -(l-e hyl-4- hydrogen, a halogen such as chloro, bromoand fluoro, Piperidylene)-m0rphamhfidine, lower alkoxy of one to fourcarbons atoms such as y p y p methoxy and ethoxy, lower alkyl of one tofour carbon y 'p p y p atoms such as methyl and ethyl, alkylsulfamylsuch as y 'P P 3 p methyl-sulfamyl and dimethylsulfamyl, thio-loweralkyl l y -p p y p such as thiomethyl and thioethyl and trifluoromethyl,R l Y 'Py" p is hydrogen or a lower alkyl of one to four carbon 1 y 'ly" y p atoms such as methyl, ethyl or propyl, B is an alkylene 1 Y PY" Yp of one to six carbon atoms, Am is l 1-(1 e y pip i y 3 5morphanthridine,

l l-( l-ethyl-3-homopiperidylene)-morphanthridine,

R2 1 l-( l-benzyl-3-homopiperidylene)- N morphanthridine, l l-(3-dimethylaminopropylidene )-morphanthridine,

40 2-chlorol 1-( 3-dimethylaminopropylidene in which R and R areselected from hydrogen, a lower morphanthridine, alkyl of one to fourcarbon atoms such as methyl, ethyl flu y m hyl minopropyor isopropyl, ora phenyl-lower alkyl of seven to 13 car- )-m0 p n i bon atoms such asbenzyl, phenethyl or phenl 3-piperazinopropylidene)flmphamhridine,ylisopropyl, or Am is a heterocyclic amino group such P p p y asmorpholino, pyrrolidino, piperidino, N-lower alkyl morphanthridine,piperazino such' as N-methyl piperazino, N-phenylz-irifluommethyl'l -P PP P lower alkyl piperazino such as N-benzyl piperazino andmorphanthridine, N-(hydroxy-lower alkyl)-piperazino groups such as 4- yy y p p p py )1- (fi-hydroxyethyl) piperazino and morphanthridine,

2-chloro-l l 3-( 4-hydroxyethylpiperazinopropymlidene)]-morphanthridine, J 2-trifluoromethyl-l l 3-(4-hydroxyethylpiperazino propylidene)]-morphanthridine, is a cyclicaminogroup such as N-lower alkyl-2,3 or 4- ll-(3-diethylaminopropylidene)-morphanthridine,

piperidyl, a 2,3 or 4-piperidyl, a N-phenyl-lower alkyl- 2-chloro-l l-(3-diethylaminopropylidene)- 2,3 or 4-piperidyl, a N-lower alkyl-2 or3-pyrrolidyl or a morphanthridine, N-phenyl-lower alkyl-2 or3-pyrrolidyl. 2-trifluoromethyl-l 1-(3-diethylaminopropylidene In thepreferred practice of the invention the hypermorphanthridine,

tensive animal is administered a safe and effectivel1-(3-methylaminopropylidene)-morphanthridine,

amount of the active ingredient in the form of its free2-chloro-1l-(3-methylaminopropylidene)- base or in the form of anontoxic acid addition salt. The morphanthridine,

active ingredient is preferably combined with one or Z-trifluoromethyl-ll-(3-methylaminopropylidene)- more pharmaceutical diluents and formedinto suitable morphanthridine,

dosage forms for oral, parental or rectal administration. 1 l-(3-dimethylaminopropyl)-morphanthridine,

The compounds employed in the present invention 2-chloro-ll-(3-dimethylaminopropyl)- may be conveniently prepared by oxidation ofthe cormorphanthridine,

8-chloro-l l-( 3-dimethylaminopropyl)- morphanthridine,

2-trifluoromethyl-l l-( 3-dimethylaminopropyl morphanthridine,

l l-( 3-diethylaminopropyl )-morphanthridine,

2-chloro-l l-( 3-diethylaminopropyl morphanthridine,

8-chlorol l-( 3-diethylaminopropyl morphanthridine,

2-trifluoromethyll l-( 3-diethylaminopropyl morphanthridine,

l l-( 3-methylaminopropyl)-morphanthridine,

2-chloro-l l-( 3-methylaminopropyl morphanthridine,

8-chlorol l-( 3-methylaminopropyl morphanthridine,

Z-trifluoromethyl-l l-( 3-methylaminopropyl morphanthridine,

l l-(N-methyl-N-benzylaminopropyl)- morphanthridine,

2-chloro-1 l-( N-methyl-N-benzylaminopropyl morphanthridine,

8-chloro-l l-(N-methyl-N-benzylaminopropyl)- morphanthridine,

2-trifluoromethyl-l l-(N-methyl-N- benzylaminopropyl)-morphanthridine,

l l-( N-methyl-piperazinopropyl)-morphanthridine,

2-chloro-l l-( N-methyl-piperazinopropyl morphanthridine,

8-chloro-l l-(N-methyl-piperazinopropyl)- morphanthridine,

morphanthridine,

l l-[ 3-( 4-hydroxyethylpiperazinopropyl morphanthridine,

2-chloro-l l- 3-( 4-hydroxyethylpiperazinopropyl) morphanthridine,

8-chloro-l l-[ 3-(4-hydroxyethylpiperazinopropyl)]- morphanthridine,

Z-trifluoromethyl-l l- 3-( 4-hydroxyethylpiperazinopropyl ]-morphanthridine,

l l-(N-methyl-4-piperidyl)-morphanthridine,

2-chloro-l l-( N-methyl-4-piperidyl morphanthridine,

8-chloro-l l-( N-methyl-4 -piperidyl morphanthridine,

Z-trifluoromethyl-l l-(N-methyl-4-piperidyl)- morphanthridine,

l l-( N-benzyl-4-piperidyl )-morphanthridine,

2-chloro-l 1-(N-benzyl-4-piperidyl)- morphanthridine,

8-chloro-l l-(N-benzyl-4-piperidyl)- morphanthridine,

2-trifluoromethyl-l l-( N-benzyl-4-piperidyl morphanthridine,

l l-(Nmethyl-3-piperidyl)-morphanthridine,

Z-chloro-l l-( N-methyl-3 -piperidyl morphanthridine,

8-chloro-l l-(N-methyl-3-piperidyl)- morphanthridine,

2-trifluoromethyl-l l-( N-methyl-3-piperidyl morphanthridine,

l l-( N-ethyl-3-pyrrolidyl )-morphanthridine,

' l l-(N-benzyl-3-pyrrolidyl)-morphanthridine,

l l-( N-methyl-B-homopiperidyl )-morphanthridine, 2-trifluoromethyl-11-[ 3-( 4-hydroxyethylpiperazinopropylidene)l-morphanthridine,

l l-( 3-diethylaminopropylidene)-morphanthridine 2-chloro-l l-(B-diethylaminopropylidene)- morphanthridine,

2-trifluoromethyl-l l-( 3-diethylaminopropylidene l l-(3-methylaminopropylidene )-morpthanthridine,

2-chloro-l l-( 3-methylaminopropylidene morphanthridine, andZ-trifluoromethyl-l l-( S-methylaminopropylidene morphanthridine. Thecompounds 2-chloro-l l-( 3- dimethylaminopropylidene)-rnorphanthridine,l l-( 1- methyl-4-piperidylene)-morphanthridine, ll-(3-dimethylaminopropylidene)-morphanthridine, and 11- 3-dimethylaminopropyl)-morphanthridine are representative of the compounds which can beemployed in the practice of the inventive method. The aforementionedcompounds, when administered intravenously in doses of 0.05 to 1.0 mg/kgof body weight to vagotomized or nonvagotomized cats, which had beenanesthetized with sodium pentobarbitol and/or chloralose, producedpronounced and sustained decreases in blood pressure.

The compounds when evaluated in sodium pentobarbitol anesthetized dogsproduced similar results. The test procedure employed included bloodpressure measurement from the right femoral artery using avolumedisplacement pressure transducer and polygraph. The compound wasadministered intravenously into the right femoral vein and blood flowwas measured by a single channel flowmeter and monitored on a polygraph.The test animals were both vagotomized and nonvagotomized dogs. In thetests the compounds produced dose related decreases in blood pressure.

The pharmaceutical compositions which may be employed are oral dosageforms such as tablets, coated or uncoated, of the immediate or thesustained release type capsules, syrups, elixirs, sterile parenteralsolutions, suppositories, or the like.

Representative of suitable pharmaceutical compositions which may beemployed in the practice of the invention are the following:

Powders (l), (2) and (3) are slugged, then granulated, mixed with (4)and (5) and tableted.

Capsules may be prepared by filling No. 3 hard gelatin capsules with thefollowing ingredients:

CAPSULES Mg. l 2-Chloro-l l-(3-dimethylaminopropylidene) morphanthridinel0 (2) Lactose U.S.P. 200 (3) Starch U.S.P. l6 (4) Talc USP. 8

The oral route is generally preferred for administering the compounds ofthis invention. However, other routes of administration such asparenteral may be employed.

In the preferred practice of the invention the patients will receivedaily doses of from 5 mg. to 500 mg. of the active ingredient. The dosesto be administered to a specific patient will, of course, depend uponmany factors, including the patients overall condition, the severity ofthe hypertension and the level at which the blood pressure is desired tobe stabilized. Generally speaking, however, the daily doses will notnormally exceed 3 mg/kg of body weight intraperitoneally. The oral dosewill run somewhat higher and the intravenous doses somewhat lower.

The following examples illustrate the preparation of representativecompounds which may be employed in the practice of the invention:

Example 1 l l-( 3-Dimethylaminopropylidene)morphanthridine To a cooledslurry of 16.4 g. (0.032 mole)'of 3-dimethylaminopropyltriphenylphosphonium bromide hydrobromide in 50 ml.of tetrahydrofuran is added with stirring 0.064 mole of butyl lithiumsolution. The mixture is stirred 1 hour at room temperature, cooled, and4.97 (0.029 mole) of ll-morphanthridone in 25 ml. of tetrahydrofuranadded dropwise. The solution is stirred for 1.5 hours at roomtemperature, refluxed for hours, cooled, 20 ml. of water added and themixture concentrated. The residue is treated with dilute aqueoushydrochloric acid and benzene, and the aqueous layer separated and madealkaline with potassium hydroxide. The resulting oil is extracted intoether, dried over potassium carbonate, filtered, concentrated, anddistilled to yield 1 l-(3-dimethyl-aminopropylidene)morphanthridine,b.p. 188200 (0.05 mm.) This base is then converted to thebis-cyclohexylsulfamate,m.p. l16-117.

Anal. Calcd. for C ,H, N,,O S C, 58.64; H, 7.30; N,

8.82. Found: C, 58.90; H, 7.55; N, 8.82.

Example 2 1 1-( 3-Dimethylaminopropylidene)morphanthridine Activemanganese dioxide g.) is stirred and refluxed with 150 ml. of benzeneusing a water separator. After 4.5 hours, 3.58 g. (0.013 mole) of 11-(3-dimethylaminopropylidene)-5,6- dihydromorphanthridine in a small amountof benzene is added and the suspension stirred and refluxed for 18hours. The MnO, is filtered off, rinsed with benzene, the filtrateconcentrated, and the residue chromatographed over 150 g. of silica geland eluted with benzene-diethylamine (40:1) to yield an oil, 11-(3-dimethylaminopropylidene)morphanthridine, which is identical to theproduct of Example 1.

Example 3 1 1-( 1-Methy1-4-piperidylene)morphanthridine A suspension of20 g. of active manganese dioxide in 200 ml. of benzene is stirred andreflux'ed for 2 hours using a water separator. When no more waterseparates a solution of 4.95 g. of 5,6-dihydro-ll-(l-methyl-4-piperidylene)morphanthridine in 50 ml. of benzene is added and thesuspension stirred and refluxed for 16 hours. The inorganic material isfiltered off, rinsed with benzene, the filtrate concentrated, and theresidue chromatographed over SiO gel using a mixture of benzene-methanol(19:1) as eluent. The appropriate fractions were combined and distilledusing a Kugelrohr apparatus to yield 1 l-( l-methyl-4-piperidylene)morphanthridine. IR absorption shows a C==N band at 6.20micron.

Anal. Calcd. for C H N z C, 83.29; H, 6.99; N, 9.71

Found: C, 83.55; H, 7.05; N, 9.73.

Example 4 2-Chloro-l 1-(3- dimethylaminopropylidene)morphanthridine To astirred refluxing mixture of 400 ml. of benzene and 36 g. of activemanganese dioxide is added 8.95 g. of2-chlorol1-(3-dimethylaminopropy1idene)-5,6- dihydromorphanthridine andthe mixture is stirred and refluxed for 6 hours using a water separator.The Mn0 is filtered off, the filtrate concentrated, distilled at highvacuum using a Kugelrohr apparatus, chromatographed over 300 g. of SiOgel and eluted with benzenemethanol (9:1 and the appropriate fractionscombined and recrystallized from 35 ml. of petroleum ether (b.p. 60-70)to yield 2chloro-1 l-(3-dimethylaminopropylidene)morphanthridine, m.p.92-93.

Anal. Calcd. for c,,H,,c1N,; C, 73.41; H, 6.16; N,

9.02;Cl, 11.41. Found: C, 73.99; H, 6.24; N, 8.92; CI, 11.49.

Example 5 1 1-( 3-Dimethylaminopropyl)morphanthridine Active manganesedioxide (25 grams) is refluxed with 250 ml. of benzene using a waterseparator. After 2 hours, 5.3 grams (0.019 mole) of 11-(3-dimethylaminopropyl)-5,6-dihydromorphanthridine in ml. of benzene isadded and the suspension stirred and refluxed for 18 hours. The MnO isfiltered off, rinsed with benzene, and the filtrate concentrated toyield the crude base. Chromatography over silica gel usingbenzene-methanol (19:1) as eluent followed by benzene-diethylamine 40: 1affords 1 l-( 3- dimethylaminopropyl)morphanthridine.

Anal. Calcd. for C I-1 M: C, 81.97; H, 7.97; N,

Found: C, 82.24; H, 8.31; N, 10.22.

lclaim:

1. A method of treating hypertension in animals which comprisesadministering to a hypertensive animal a safe and effective amount of acompound of the formula in which X and Y are hydrogen, halogen, loweralkoxy of one to four carbon atoms, lower alkyl of one to four carbonatoms, thiolower alkyl, alkyl sulfamyl and trifluoromethyl, R ishydrogen or lower alkyl of one to four carbon atoms, B is an alkylene ofone to six carbon atoms, and R2 and R are hydrogen, alkyl of one to fourcarbon atoms or phenyl lower alkyl of ent V9a b9n at ms- 2. The methodof claim 1 in 3. The method of claim 1 inwhich R, X and Y are aremethyl.

2. The method of claim 1 in which R is hydrogen.
 3. The method of claim1 in which R, X and Y are hydrogen.
 4. The method of claim 1 in which R,X and Y are hydrogen, B is propylene, and R2 and R3 are hydrogen orlower alkyl.
 5. The method of claim 1 in which R, X and Y are hydrogen,B is propylene, and R2 and R3 are methyl.
 6. The method of claim 1 inwhich R and X are hydrogen, Y is 2-chloro, B is propylene, and R2 and R3are methyl.